SCD is a genetic blood disorder characterized by abnormal hemoglobin S (HbS) synthesis with sickle cell anemia (SCA) as the most common subtype. Stroke is the most frequent cause of death and long-term disability in both children and adults with SCD. Studies of patients with focal neurologic deficits have revealed abnormalities of both large and small vessels in SCD. Currently, the main clinical screening test is the use of transcranial Doppler (TCD) for neurologically asymptomatic children with SCD. The TCD test has a low positive predictive value and is not effective to screen stroke risk in adult SCD patients. Cerebral blood flow (CBF), a measure of the microvascular perfusion of the brain, has been recognized as a potentially more sensitive and specific indicator of early cerebrovascular impairment in both children and adults with SCD. CBF measurement based on the arterial spin labeling (ASL) MRI technique is promising as it does not require a contrast agent and is free of radiation. However, the existing ASL techniques often acquire 2D multi-slice perfusion-weighted MRI at a single post-labeling delay and, for CBF calculation, make assumptions on a number of parameters that are related to blood properties, such as arterial arrival time (AAT), longitudinal relaxation time (T1) of blood and labeling efficiency. The overall goal of the research proposed is to develop and validate a multi-delay 3D ASL protocol combined with per-subject measurements of blood T1 and labeling efficiency, which provides accurate and reliable perfusion metrics (CBF and AAT) for SCD patients. The measured CBF and AAT are expected to allow detection of both small and large vessel disease simultaneously for SCD. The specific aims of this study is first to develop a comprehensive and fast ASL-based perfusion protocol and demonstrate its reliability and reproducibility in healthy volunteers (Aim 1), then to validate the measured CBF and AAT with phase-contrast MR Angiography (PC-MRA) and dynamic susceptibility contrast (DSC) MRI in a group of SCA patients without a history of stroke (Aim 2), and finally to monitor CBF and AAT in patients with SCD and a history of stroke to explore the association between CBF and AAT and recurrent brain injury (Aim 3).